EXCEED THE SPACE PROVIDED. Superantigens are lethal toxins that in sublethal amounts incapacitate, posing a bioterror threat. This project aims to take a potent, broadly effective peptide antagonist with demonstrated capability of blocking superantigen-induced toxic shock in two animal models (mouse, pig) through preclinical development up to (NO filing, with the participation of several US companies. Using unique insight into superantigen action, we designed peptides that inhibit induction of a T helper 1 cytokine storm by divergent superantigen toxins and protect mice from lethal toxic shock, even when given post-challenge. Treatment with the antagonist suppresses incapacitation in a quantitative pig model for superantigen-induced symptoms close to man. One prototype lead antagonist is a mimetic of a conservedsuperantigen domain remote from binding sites for MHC II molecule and T cell receptor. Superantigens use this domain to bind an additional receptor, now proven critical for induction of a Th1 response: blocking this interaction is sufficient to prevent toxic shock. The antagonist blocks binding of superantigen to this receptor, inhibiting the Th1 response yet leaving the Th2 response intact to permit induction of protective immunity. Peptides derived from the superantigen binding site in the receptor also are potent antagonists that protect mice and pigs from toxic shock. Thus, two distinct classes of antagonists are in hand: superantigen mimetics and superantigen receptor mimetics. Identification of the receptor creates a platform for generating optimized antagonists and for understanding antagonist mode of action. A cooperative effort of the NIAID, the PI, Atox Bio Ltd., Tel Aviv University as subcontractor and US and UK vendors is timely for developing a mature lead compound from the two antagonist classes towards a FDA-approved broad anti-toxin therapeutic under the 'Animal Rule'. A pre- pre-IND meeting in 2004 validated the regulatory strategy for proposed product development. The work aims to optimize leads and to elucidate mechanism of antagonist action as part of the approval process. Molecular and biological activity characterizations will be performed to select one lead for nonclinical studies and cGMP manufacturing. The pig model will be characterized as efficacy model that will become, with nonhuman primate studies, part of the NDA for this product. Product development to be completed is selection of a lead compound, evaluated by pig and nonhuman primate efficacy models, up to IND filing for a Phase 1a clinical trial. A superantigen therapeutic resulting from the proposed effort offers a special opportunity in biodefense. PERFORMANCE SITE ========================================Section End===========================================